PGC-1α and PGC-1β Increase Protein Synthesis via ERRα in C2C12 Myotubes.

The transcriptional coactivators peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) and PGC-1 beta are positive regulators of skeletal muscle mass and energy metabolism; however, whether they influence muscle growth and metabolic adaptations via increased protein synthesis is not clear. This study revealed PGC-1 alpha or PGC-1 beta overexpression in C2C12 myotubes increased protein synthesis and myotube diameter under basal conditions and attenuated the loss in protein synthesis following the treatment with the catabolic agent, dexamethasone. To investigate whether PGC-1 alpha or PGC-1 beta signal through the Akt/mTOR pathway to increase protein synthesis, treatment with the PI3K and mTOR inhibitors, LY294002 and rapamycin, respectively, was undertaken but found unable to block PGC-1 alpha or PGC-1 beta's promotion of protein synthesis. Furthermore, PGC-1 alpha and PGC-1 beta decreased phosphorylation of Akt and the Akt/mTOR substrate, p70S6K. In contrast to Akt/mTOR inhibition, the suppression of ERR a, a major effector of PGC-1 alpha and PGC-1 beta activity, attenuated the increase in protein synthesis and myotube diameter in the presence of PGC-1 alpha or PGC-1 beta overexpression. To characterize further the biological processes occurring, gene set enrichment analysis of genes commonly regulated by both PGC-1 alpha and PGC-1 beta was performed following a microarray screen. Genes were found enriched in metabolic and mitochondrial oxidative processes, in addition to protein translation and muscle development categories. This suggests concurrent responses involving both increased metabolism and myotube protein synthesis. Finally, based on their known function or unbiased identification through statistical selection, two sets of genes were investigated in a human exercise model of stimulated protein synthesis to characterize further the genes influenced by PGC-1 alpha and PGC-1 beta during physiological adaptive changes in skeletal muscle.